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Creating my niche in grad school

How diversity and outreach initiatives helped me find my place in MIT

YamilexA.-S.
November 15, 2019

Imagine being in a roller coaster that’s on fire, adrift, going full speed. That was my first year at MIT. Coming straight from an undergraduate institution in Puerto Rico, it was difficult for me to get used to the fast pace in which topics were taught in a different language and to the amount of work we had to constantly do. Recognizing these struggles, I convinced myself that I had to work even harder. However, towards the end of my first year, I couldn’t help but feel like something was missing. While struggling with that inner voice, I stumbled one day upon my personal statement for graduate school applications. I remember thinking, “who wrote this?”. One sentence in particular felt completely foreign to me: “I wish to provide a voice and an example that encourages minority students to pursue a career in science.” How was it that one year into my PhD program, I had completely lost the drive to start paving the path for people that looked and felt like me?

Being in STEM, it is quite easy to feel that if science isn’t the most important thing in your life, you are probably doing something wrong. For me, however, although science is definitely an important part of my life, it surely isn’t my entire life. I realize this isn’t a popular view among my peers, especially at a place like MIT, and it took some time for me to even embrace this mentality. I knew I appreciated my science more when I started doing things that fulfilled me outside the lab. This was clear in my mind, but I didn’t know where to start. How could I begin creating my niche in grad school?

While talking to a friend of mine about my interest in getting involved in diversity initiatives, I learn about a graduate student group called the Biology Diversity Community (BDC). The main mission of this group was to help foster networking amongst underrepresented graduate students in the biology community and connect students to resources that may be helpful. As it turned out, they were looking for volunteers to help plan out activities for the upcoming academic year. I reached out to the organizers, who listened to my ideas on how to create a healthy environment for students with a diverse array of backgrounds. They must have liked those ideas, since they then allowed me to carry out some activities for the semester including one for the MIT Summer Research Program (MSRP).

The MSRP is a summer program that enables undergraduate students from all over the country to conduct cutting-edge research at MIT, especially those from disadvantaged or underrepresented groups. My idea was to host a BDC-MSRP mixer to encourage summer students to interact with the greater MIT Biology community. A few days into the planning of the event, I started having doubts and worrying that very few people would actually show up. In between sending emails, ordering food, and publicizing the event, this thought kept haunting me. I wanted the mixer to be a success, not only because this was my first time planning an event of this magnitude, but also because this was part of fulfilling my major goal at MIT. I wanted to give back to the community that allowed me to be where I am today.

When the day of the event came, I was happy and reassured to see roughly 50 people show up, including post-docs, graduate students, and faculty! Many interns thanked me for the event, saying it made them feel like they were part of the community. I had a chance to speak with people from my program that I didn’t even know, and learned more about their lives and their experience in the department. Overall, I was genuinely excited my event was helpful for both the interns and the department.  

Enabling the bonding between upper year grad students and prospective students led me to become an organizer for BioPals. BioPals’ main goal is to increase communication amongst biology graduate students from all levels. First-year graduate students get paired with upper-year students (aka, “Pals”) to meet on a monthly basis and interact with other pairs during social events. I was part of the kickoff year as a BioPals mentee, which made my first semester here more bearable. My biopal was a fifth-year student that gave me all the pointers I needed to survive my first year. She went the extra mile to ensure I was ok, from giving me a gift after I passed my first round of exams, to staying with me for over an hour when I was having an anxiety attack. She really inspired me to become a resource for incoming first-years. I currently work on organizing BioPals along with 4 other students from my year. BioPals is now starting its second year, with more social events and roughly an 80% participation rate from first-year students.

With all these activities, I feel a sense of purpose by doing something that matters to me. That sentence in my personal statement doesn’t feel that foreign to me anymore. I can safely say that I have “provided a voice and an example that encourages minority students” to pursue a career in science. I feel happy I am able to do the two things I love during my graduate school trajectory: helping others and doing science!

I could continue talking about my niche forever, but I want to take some time to address yours! I have found that diversity and outreach are some of the things that keep me sane and happy in graduate school. If your niche is mentoring, policy, or startups, (or anything), make some time for that! Graduate school is long. You can run your experiment the next day or troubleshoot that equipment piece later. Make your graduate experience one that is worth looking back on. And I hope in no time, you’ll create your own niche in grad school!

Scholarships Open Up Learning Opportunities at MIT
MIT Better World
November 18, 2019

When Muskaan Aggarwal ’20 was considering colleges, she was looking for undergraduate research opportunities and a strong humanities program. “Choosing MIT was a convergence of factors,” she says. “I knew that there’s no better place for biological research than Cambridge, but I did not know that MIT students are required to take eight humanities classes over their four years. It was so surprising to learn that it’s built into the degree!”

And there was another important draw to the netbet sports bettingInstitute: “Scholarship support was a big factor in me coming to MIT because I probably would not have been able to afford it otherwise,” says Aggarwal, who is a recipient of the Malcolm E. and Donna M. Wheeler Scholarship. As one of five universities in the country with need-blind admissions for both US and international students, MIT is committed to meeting the full financial need of every accepted undergraduate through scholarships. “My scholarship has made it possible for me to pursue extracurriculars based on my passions,” she continues. “It would be much more difficult to participate in those experiences if I had to support myself by working multiple jobs.”

In addition to majoring in biology, Aggarwal minors in ancient and medieval studies and participates in the Burchard Scholars Program, which facilitates monthly faculty-led humanities seminars. “To be a good scientist, you need to be able to communicate your work very effectively, and you cannot do that without a humanities background,” she says, noting that her minor and major intersect in interesting ways. “With ancient and medieval studies, we have very little evidence with which to reconstruct the past, so imagination is key. It’s similar with biology—we’ve learned so much but there’s still so much we don’t know; we have to combine existing knowledge with imagination to construct the future.”

Since her first year at MIT, Aggarwal has been working in the lab of Angelika Amon, who is the Kathleen and Curtis Marble Professor in Cancer Research, through the Undergraduate Research Opportunities Program. “In Professor Amon’s lab, I’ve been fortunate to be able to work with Marianna Trakala [postdoc researcher], an incredible mentor, since the infancy of the project. Our project explores how deviation from the normal chromosome number can lead to tumorigenesis,” Aggarwal says.

Aggarwal is planning to become a physician-scientist to pursue both patient care and research—her “true love”—but she is also looking for ways to integrate her other passions into her future profession. She sees MIT as the ideal place to explore a wide range of interests—and the scholarship support she receives is a vital component of her education. “MIT is an extraordinary place. In high school, I never imagined that I would be minoring in ancient and medieval studies, or dancing with middle school girls on Monday afternoons as a SHINE mentor, or writing a review of a Dutch film about a famous Swedish author for The Tech,” she says. “I could have done research at other schools, but would I be working in the lab of someone like Professor Amon, who won nearly every single big prize in science in the past year? I’m immensely grateful that the scholarship has given me the opportunity to explore all of my interests during college.”

New pathway for lung cancer treatment

MIT researchers identify pyrimidine biosynthesis as a target for the treatment of small cell lung cancer.

Bendta Schroeder | Koch Institute
November 11, 2019

MIT cancer biologists have identified a new therapeutic target for small cell lung cancer, an especially aggressive form of lung cancer with limited options for treatment.

Lung cancer is the leading cause of cancer-associated mortality in the United States and worldwide, with a five-year survival rate of less than 20 percent. But of the two major sub-types of lung cancer, small cell and non-small cell, small cell is more aggressive and has a much poorer prognosis. Small cell lung cancer tumors grow quickly and metastasize early, resulting in a five-year survival rate of about 6 percent.

“Unfortunately, we haven’t seen the same kinds of new treatments for small cell lung cancer as we have for other lung tumors,” says Tyler Jacks, director of the Koch Institute for Integrative Cancer Research at MIT. “In fact, patients are treated today more or less the same way they were treated 40 or 50 years ago, so clearly there is a great need for the development of new treatments.”

A study appearing in the Nov. 6 issue of Science Translational Medicine shows that small cell lung cancer cells are especially reliant on the pyrimidine biosynthesis pathway and that an enzyme inhibitor called brequinar is effective against the disease in cell lines and mouse models.

Jacks is the senior author of this study. Other MIT researchers include Associate Professor of Biology and Koch Institute member Matthew Vander Heiden, and co-lead authors postdoc researcher Leanne Li and graduate student Sheng Rong Ng.

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Researchers in the Jacks lab used CRISPR to screen small cell lung cancer cell lines for genes that already have drugs targeting them, or that are likely to be druggable, in order to find therapeutic targets that can be tested more quickly and easily in a clinical setting.

The group found that small cell lung cancer tumors are particularly sensitive to the loss of a gene encoding dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine biosynthesis pathway. Upon discovering that the sensitivity involved a metabolic pathway, the researchers sought the collaboration of the Vander Heiden lab, experts in normal and cancer cell metabolism who were already conducting studies on the role of pyrimidine metabolism and DHODH inhibitors in other cancers.

Pyrimidine is one of the major building blocks of DNA and RNA. Unlike healthy cells, cancer cells are constantly dividing and need to synthesize new DNA and RNA to support the production of new cells. The investigators found that small cell lung cancer cells have an unexpected vulnerability: Despite their dependence on the availability of pyrimidine, this synthesis pathway is much less active in small cell lung cancer cells than in other types of cancer cells examined in the study. Through inhibiting DHODH, they found that small cell lung cancer cells were not able to produce enough pyrimidine to keep up with demand.

When researchers treated a genetically engineered mouse model of small cell lung cancer tumors with the DHODH inhibitor brequinar, tumor progression slowed down and the mice survived longer than untreated mice. Similar results were observed for small cell lung cancer tumors in the liver, a frequent site of metastasis in patients.

In addition to mouse model studies, the researchers tested four patient-derived small cell lung cancer tumor models and found that brequinar worked well for two of these models — one of which does not respond to the standard platinum-etoposide regimen for this disease.

“These findings are noteworthy because second-line treatment options are very limited for patients whose cancers no longer respond to the initial treatment, and we think that this could potentially represent a new option for these patients,” says Ng.

Shorter pathway to the clinic

Brequinar has already been approved for use in patients as an immunosuppressant, and there has been some preclinical research showing that brequinar and other DHODH inhibitors may be effective for other types of cancers.

“We’re excited because our findings could provide a new way to help small cell lung cancer patients in the future,” says Li. “While we still have a lot of work to do before brequinar can be tested in the clinic as a therapy for small cell lung cancer, we’re hopeful that this might happen more quickly now that we’re starting with a drug that is known to be safe in humans.”

Next steps for the researchers include optimizing the therapeutic efficacy of DHODH inhibitors and combining them with other currently available treatment options for small cell lung cancer, such as chemotherapy and immunotherapy. To help clinicians tailor treatments to individual patients, researchers will also work to identify biomarkers for tumors that are susceptible to this therapy, and investigate resistance mechanisms in tumors that do not respond to this treatment.

The research was funded, in part, by the MIT Center for Precision Cancer Medicine and the Ludwig Center for Molecular Oncology at MIT.

Researchers discover a new toxin that impedes bacterial growth
Raleigh McElvery
November 6, 2019

An international research collaboration has discovered a new toxin, which bacteria inject into their neighboring cells to hinder growth and compete for limited resources. Their findings were published on November 6 in Nature.

At McMaster University in Ontario, Canada, co-senior author John Whitney and his team were studying a secretion system that allows bacteria to deliver NetBet live casinothese deleterious molecules, when they came across a new toxin. This toxin was an enzyme, and one they had never seen before. Based on their structural analyses, it looked a lot like the enzymes that synthesize guanosine tetra- and penta-phosphate, collectively known as “(p)ppGpp.” (p)ppGpp is a signaling molecule that helps bacteria safely dial down their growth rate in response to starvation. Suspecting the toxin might produce (p)ppGpp in recipient cells and ultimately impact their growth, the McMaster team shared their findings with Michael Laub, a professor of biology at MIT and a Howard Hughes Medical Institute investigator.

Researchers identified Tas1 in Pseudomonas aeruginosa bacteria. Credit: U.S. Centers for Disease Control and Prevention – Medical Illustrator.

Boyuan Wang, a postdoc in the Laub lab who specializes in (p)ppGpp synthesis, examined the unknown enzyme’s activity to determine its product. He soon realized that, rather than making (p)ppGpp, this enzyme was instead producing related molecules, adenosine tetraphosphate and adenosine pentaphosphate, collectively referred to as (p)ppApp. Somehow, (p)ppApp production was hindering growth.

“Scientists have known about (p)ppApp for decades, but it hadn’t been shown to have a physiological role in organisms until now,” says Wang, a co-first author. Researchers had previously speculated that (p)ppApp was merely a non-specific product generated during (p)ppGpp synthesis, so it was surprising to find an enzyme that made it specifically.

The researchers named their enzyme Tas1, and determined that it uses the cell’s main energy currency, ATP, and its precursor, ADP, to produce (p)ppApp. In fact, one molecule of Tas1 was enough to consume 180,000 molecules of ATP per minute — two orders of magnitude faster than the fastest known (p)ppGpp synthetases work to make (p)ppGpp. Using metabolomic analyses, the MIT group showed that this exceptional rate of (p)ppApp production requires so much energy that there’s not enough left to carry out essential cellular processes, effectively killing the bacterium.

“Bacteria can inject only one Tas1 molecule at a time, and yet the toxin has such a powerful impact on its target, depleting the ATP supply in a matter of minutes,” Wang says. “The secretion system is kind of like a miniaturized intercontinental ballistic missile in terms of its structure and impact, except it functions ‘intercompartmentally’ between two bacteria.”

“It’s amazing that the first (p)ppApp synthase ever discovered actually serves as a novel, and quite clever, means of killing another cell,” says Laub, a co-senior author. “Findings like these really highlight the diversity of mechanisms that bacteria use to inhibit each other’s growth.”

Tas1, the researchers believe, may augment other known toxins that bacteria inject into one another to hinder cell growth, including those that work in the cytoplasm or target the cell envelope.

As a biochemist, Wang is excited by the prospect of using Tas1 as a tool in future experiments to deplete ATP, and probe the networks of metabolic regulation within bacteria and higher organisms.

“It’s fascinating to uncover the strategies nature uses to repurpose proteins,” Wang says. “Before this study, we wouldn’t have considered the possibility that a member of this protein family could be used as a deadly toxin.”

Image: Tas1, a newly discovered enzyme, has a similar structure to the widespread bacterial Rel proteins that produce (p)ppGpp to promote survival during starvation. Tas1 alters its specificity to quickly produce large amounts of (p)ppApp, serving as a toxin in Pseudomonas aeruginosa and killing competing bacteria. Credit: Boyuan Wang.

Citation:
“An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp”
Nature, online November, 6, DOI: 10.1038/s41586-019-1735-9
Shehryar Ahmad, Boyuan Wang, Matthew D. Walker, Hiu-Ki R. Tran, Peter J. Stogios, Alexei Savchenko, Robert A. Grant, Andrew G. McArthur, Michael T.  Laub, and John C. Whitney.

School of Science appoints 14 faculty members to named professorships

Those selected for these positions receive additional support to pursue their research and develop their careers.

School of Science
November 4, 2019

The School of Science has announced that 14 of its faculty members have been appointed to named professorships. The faculty members selected for these positions receive additional support to pursue their research and develop their careers.

Riccardo Comin is an assistant professor in the Department of Physics. He has been named a Class of 1947 Career Development Professor. This three-year professorship is granted in recognition of the recipient’s outstanding work in both research and teaching. Comin is interested in condensed matter physics. He uses experimental methods to synthesize new materials, as well as analysis through spectroscopy and scattering to investigate solid state physics. Specifically, the Comin lab attempts to discover and characterize electronic phases of quantum materials. Recently, his lab, in collaboration with colleagues, discovered that weaving a conductive material into a particular pattern known as the “kagome” pattern can result in quantum behavior when electricity is passed through.

Joseph Davis, assistant professor in the Department of Biology, has been named a Whitehead Career Development Professor. He looks at how cells build and deconstruct complex molecular machinery. The work of his lab group relies on biochemistry, biophysics, and structural approaches that include spectrometry and microscopy. A current project investigates the formation of the ribosome, an essential component in all cells. His work has implications for metabolic engineering, drug delivery, and materials science.

Lawrence Guth is now the Claude E. Shannon (1940) Professor of Mathematics. Guth explores harmonic analysis and combinatorics, and he is also interested in metric geometry and identifying connections between geometric inequalities and topology. The subject of metric geometry revolves around being able to estimate measurements, including length, area, volume and distance, and combinatorial geometry is essentially the estimation of the intersection of patters in simple shapes, including lines and circles.

Michael Halassa, an assistant professor in the Department of Brain and Cognitive Sciences, will hold the three-year Class of 1958 Career Development Professorship. His area of interest is brain circuitry. By investigating the networks and connections in the brain, he hopes to understand how they operate — and identify any ways in which they might deviate from normal operations, causing neurological and psychiatric disorders. Several publications from his lab discuss improvements in the treatment of the deleterious symptoms of autism spectrum disorder and schizophrenia, and his latest news provides insights on how the brain filters out distractions, particularly noise. Halassa is an associate investigator at the McGovern Institute for Brain Research and an affiliate member of the Picower Institute for Learning and Memory.

Sebastian Lourido, an assistant professor and the new Latham Family Career Development Professor in the Department of Biology for the next three years, works on treatments for infectious disease by learning about parasitic vulnerabilities. Focusing on human pathogens, Lourido and his lab are interested in what allows parasites to be so widespread and deadly, looking on a molecular level. This includes exploring how calcium regulates eukaryotic cells, which, in turn, affect processes such as muscle contraction and membrane repair, in addition to kinase responses.

Brent Minchew is named a Cecil and Ida Green Career Development Professor for a three-year term. Minchew, a faculty member in the Department of Earth, Atmospheric and Planetary Sciences, studies glaciers using remote sensing methods, such as interferometric synthetic aperture radar. His research into glaciers, including their mechanics, rheology, and interactions with their surrounding environment, extends as far as observing their responses to climate change. His group recently determined that Antarctica, in a netbet sports bettingworst-case scenario climate projection, would not contribute as much as predicted to rising sea level.

Elly Nedivi, a professor in the departments of Brain and Cognitive Sciences and Biology, has been named the inaugural William R. (1964) And Linda R. Young Professor. She works on brain plasticity, defined as the brain’s ability to adapt with experience, by identifying genes that play a role in plasticity and their neuronal and synaptic functions. In one of her lab’s recent publications, they suggest that variants of a particular gene may undermine expression or production of a protein, increasing the risk of bipolar disorder. In addition, she collaborates with others at MIT to develop new microscopy tools that allow better analysis of brain connectivity. Nedivi is also a member of the Picower Institute for Learning and Memory.

Andrei Negut has been named a Class of 1947 Career Development Professor for a three-year term. Negut, a member of the Department of Mathematics, fixates on problems in geometric representation theory. This topic requires investigation within algebraic geometry and representation theory simultaneously, with implications for mathematical physics, symplectic geometry, combinatorics and probability theory.

Matĕj Peč, the Victor P. Starr Career Development Professor in the Department of Earth, Atmospheric and Planetary Science until 2021, studies how the movement of the Earth’s tectonic plates affects rocks, mechanically and microstructurally. To investigate such a large-scale topic, he utilizes high-pressure, high-temperature experiments in a lab to simulate the driving forces associated with plate motion, and compares results with natural observations and theoretical modeling. His lab has identified a particular boundary beneath the Earth’s crust where rock properties shift from brittle, like peanut brittle, to viscous, like honey, and determined how that layer accommodates building strain between the two. In his investigations, he also considers the effect on melt generation miles underground.

Kerstin Perez has been named the three-year Class of 1948 Career Development Professor in the Department of Physics. Her research interest is dark matter. She uses novel analytical tools, such as those affixed on a balloon-borne instrument that can carry out processes similar to that of a particle collider (like the Large Hadron Collider) to detect new particle interactions in space with the help of cosmic rays. In another research project, Perez uses a satellite telescope array on Earth to search for X-ray signatures of mysterious particles. Her work requires heavy involvement with collaborative observatories, instruments, and telescopes. Perez is affiliated with the Kavli Institute for Astrophysics and Space Research.

Bjorn Poonen, named a Distinguished Professor of Science in the Department of Mathematics, studies number theory and algebraic geometry. He, his colleagues, and his lab members generate algorithms that can solve polynomial equations with the particular requirement that the solutions be rational numbers. These types of problems can be useful in encoding data. He also helps to determine what is undeterminable, that is exploring the limits of computing.

Daniel Suess, named a Class of 1948 Career Development Professor in the Department of Chemistry, uses molecular chemistry to explain global biogeochemical cycles. In the fields of inorganic and biological chemistry, Suess and his lab look into understanding complex and challenging reactions and clustering of particular chemical elements and their catalysts. Most notably, these reactions include those that are essential to solar fuels. Suess’s efforts to investigate both biological and synthetic systems have broad aims of both improving human health and decreasing environmental impacts.

Alison Wendlandt is the new holder of the five-year Cecil and Ida Green Career Development Professorship. In the Department of Chemistry, the Wendlandt research group focuses on physical organic chemistry and organic and organometallic synthesis to develop reaction catalysts. Her team fixates on designing new catalysts, identifying processes to which these catalysts can be applied, and determining principles that can expand preexisting reactions. Her team’s efforts delve into the fields of synthetic organic chemistry, reaction kinetics, and mechanics.

Julien de Wit, a Department of Earth, Atmospheric and Planetary Sciences assistant professor, has been named a Class of 1954 Career Development Professor. He combines math and science to answer questions about big-picture planetary questions. Using data science, de Wit develops new analytical techniques for mapping exoplanetary atmospheres, studies planet-star interactions of planetary systems, and determines atmospheric and planetary properties of exoplanets from spectroscopic information. He is a member of the scientific team involved in the Search for habitable Planets EClipsing ULtra-cOOl Stars (SPECULOOS) TRANsiting Planets and Planetesimals Small Telescope (TRAPPIST), made up of an international collection of observatories. He is affiliated with the Kavli Institute.

MicroRNAs work together to tune gene expression in the brain
Raleigh McElvery
November 4, 2019

A new study from the MIT Department of Biology suggests we may need to re-think how certain RNAs operate to impact development and disease.

According to the “central dogma” of biology, DNA is converted into messenger RNA (mRNA) before being expressed as a protein. However, not all RNAs are destined to become proteins. MicroRNAs (miRNAs) are small, non-coding RNAs, which regulate a variety of cellular processes by binding to mRNAs and destabilizing them to reduce their expression.

A single miRNA can target hundreds of different mRNAs. And yet, on its own, an individual miRNA only represses the expression of each mRNA target by about 10-20%. Given that the effects of a single miRNA are so mild, researchers couldn’t understand how they could exert such powerful control over so many processes. One theory is that, rather than acting alone, perhaps multiple miRNAs bind to the same target mRNA in concert to exert enhanced repression. However, few studies have explored this idea in-depth, or identified examples of such co-regulation.

In a new study published in Genome Research on October 24, MIT biologists were able to pinpoint specific miRNAs that collaborate with one another to repress mRNA expression in the brain — adding credence to the notion that miRNAs often collaborate with one another.

“The idea that miRNAs may work by co-targeting sets of transcripts together has been around for a while,” says Jennifer Cherone, the study’s lead author. “But it’s only recently that certain key advances — like better annotations of where transcripts end and more accurate predictions of miRNA target sites — have allowed us to uncover these relationships and rigorously test them in the lab.”

Using powerful computational analyses to compare target sets of different miRNAs, Cherone was able to identify hundreds of distinct miRNAs, which — despite their sequence differences — bound many of the same mRNAs. Of all the tissues she examined, the brain appeared to have the most co-targeting. So she narrowed her focus to explore the overlapping functions of just two miRNAs that worked together there: miR-138 and miR-137.

“That was a really interesting observation and a functional demonstration of the overlap between these two miRNAs,” she says. “One miRNA can rescue the loss of a completely different miRNA if they share targets.”If she deleted miR-138 from her cells, they could no longer differentiate and become neurons. However, when she added miR-138’s co-targeting partner, miR-137, the cells were once again able to differentiate.

Cherone went on to identify an entire group of miRNAs within the brain, nine in total, that also shared similar targets. She selected several genes targeted by three or more of these miRNAs, and mutated every possible combination of the miRNA sites to determine their individual contributions. She ultimately established that subsets of the miRNAs could repress gene expression between five- and tenfold if they were expressed at the same time and bound close together.

According to Cherone, “seeing a tenfold repression by miRNAs is unheard of.” Such strong repression can NetBet sporthave serious phenotypic consequences. She attributes this finding to the lab’s advanced computational strategies, which allowed them to systematically and unbiasedly identify the miRNAs that work together and their gene targets.

Why might a single gene be regulated by so many different miRNAs? There are more evolutionary paths to acquire sites for many different miRNAs than paths to acquire sites for the same miRNA. And, the authors explain, this arrangement may allow more precise control of cell type-specific expression.

Given that their miRNAs of interest primarily worked in the brain, the researchers wondered why this tissue might require so much co-targeting. One idea is that mRNAs in the brain tend to have longer regions where more miRNAs can bind to exert their effects. Another possibility is that mRNA expression in the brain must be especially fine-tuned, because too much or too little expression could have severe ramifications for neuronal function and development. For instance, fragile X-associated tremor/ataxia syndrome (FXTAS) can result from fairly subtle changes in proteins levels.

“Co-targeting appears to be widespread in many tissues, not just the brain,” says senior author Christopher Burge, a professor of biology at MIT. “This means that strategies to modulate the activity of a miRNA in a genetic or therapeutic context will be most effective when they take into account the levels of the other miRNAs that frequently partner with the miRNA of interest.”

“It’s time to start thinking of miRNAs as working together in networks, rather than functioning as individual units,” Cherone says. “If you want to know the function of a given miRNA, you have to understand the group it’s collaborating with, and explore its function within that group.”

Top image: Graphical illustration of co-targeting by miRNAs. Credit: Jennifer Cherone.

Citation:
“Cotargeting among microRNAs in the brain.”
Genome Research, online October 24, 2019, DOI: 10.1101/gr.249201.119
Jennifer M. Cherone, Vjola Jorgji, and Christopher B. Burge.

Golden Anniversary for Luria’s Gold Medal
Koch Institute
October 22, 2019

Fifty years ago, on the heels of an extraordinary summer—the Cuyahoga River Fire, Stonewall Riots, Apollo 11, Manson and Woodstock—a microbiologist in Cambridge, Massachusetts received one more heady piece news. Originally from Torino, Italy, Salvador E. Luria had joined the faculty of MIT ten years earlier. It was here in the US, where he immigrated in 1940, that he conducted the research that had just won him the Nobel Prize.

Luria, with collaborators Max Delbrück and Alfred Hershey, won the Nobel in Medicine for discoveries about the replication mechanism and genetic structure of viruses called bacteriophages. Luria also showed that bacterial resistance to these viruses is genetically inherited, uncovering mutations that permit them to overcome immunological barriers.The scientists’ work illuminated key unanswered questions in virology and genetics, pioneered biological materials and techniques, and is regarded as being primarily responsible for modern advances in the control of viral diseases and for advances in molecular biology.

By time of his award, however, Luria was looking for new challenges, and shortly after the passage of the National Cancer Act of 1971 he successfully applied for funds to build a cancer research facility at MIT.  As founder and first director of the fledgling MIT Center for Cancer Research (CCR), he oversaw the conversion of a former chocolate factory abutting campus into a research laboratory and National Cancer Institute-designated basic cancer research center; he also sought out and recruited scientists with expertise in genetics, immunology, and cell biology. Luria and his founding faculty opened the CCR in 1974, setting in motion an unprecedented era of progress in cancer research.  Under his leadership, the Center set the standard for investigating the fundamental nature of cancer.  Among their accomplishments, faculty members isolated the first human oncogene, discovered RNA splicing, and made numerous other seminal contributions to cancer biology and genetics.  Beyond their importance in understanding the disease, these advances laid the groundwork for new methods to treat and diagnose cancer.  At institutions around the world, generations of CCR-trained scientists have shaped the evolution of cancer research in their own labs.  Here at MIT, the legacy of Luria and the CCR continues to flourish through the work of the Koch Institute for Integrative Cancer Research, where cancer scientists and engineers collaborate to create the next generation of cancer solutions.

As a tribute to the individual who spearheaded the formation of MIT’s first dedicated cancer research effort the Koch Institute is working, with friends and the MIT administration, to name the Koch Institute’s main meeting space the Salvador E. Luria Auditorium.  A hub of daily life in the Koch Institute, the Luria Auditorium will host scientific and community meetings and programs, visiting presenters, K-12 educational workshops, and special and public events. The Luria Auditorium will also include an installation describing the history of the CCR and its many contributions to cancer science.

Contributions to the campaign to name the Salvador E. Luria Auditorium can be made online or by mail to Lisa Marks Schwarz, Managing Director of Development, Koch Institute at MIT, 77 Massachusetts Avenue (76-158), Cambridge, MA 02139. Your support will help to ensure that the pioneering work of Luria and the CCR remain a living legacy within the heart of the Koch Institute.

Biologists build proteins that avoid crosstalk with existing molecules

Engineered signaling pathways could offer a new way to build synthetic biology circuits.

Anne Trafton | MIT News Office
October 23, 2019

Inside a living cell, many important messages are communicated via interactions between proteins. For these signals to be accurately relayed, each protein must interact only with its specific partner, avoiding unwanted crosstalk with any similar proteins.

A new MIT study sheds light on how cells are able to prevent crosstalk between these proteins, and also shows that there remains a huge number of possible protein interactions that cells have not used for signaling. This means that synthetic biologists could generate new pairs of proteins that can act as artificial circuits for applications such as diagnosing disease, without interfering with cells’ existing signaling pathways.

“Using our high-throughput approach, you can generate many orthogonal versions of a particular interaction, allowing you to see how many different insulated versions of that protein complex can be built,” says Conor McClune, an MIT graduate student and the lead author of the study.

In the new paper, which appears today in Nature, the researchers produced novel pairs of signaling proteins and demonstrated how they can be used to link new signals to new outputs by engineering E. coli cells that produce yellow fluorescence after encountering a specific plant hormone.

Michael Laub, an MIT professor of biology, is the senior author of the study. Other authors are recent MIT graduate Aurora Alvarez-Buylla and Christopher Voigt, the Daniel I.C. Wang Professor of Advanced Biotechnology.

New combinations

In this study, the researchers focused on a type of signaling pathway called two-component signaling, which is found in bacteria and some other organisms. A wide variety of two-component pathways has evolved through a process in which cells duplicate genes for signaling proteins they already have, and then mutate them, creating families of similar proteins.

“It’s intrinsically advantageous for organisms to be able to expand this small number of signaling families quite dramatically, but it runs the risk that you’re going to have crosstalk between these systems that are all very similar,” Laub says. “It then becomes an interesting challenge for cells: How do you maintain the fidelity of information flow, and how do you couple specific inputs to specific outputs?”

Most of these signaling pairs consist of an enzyme called a kinase and its netbet sports bettingsubstrate, which is activated by the kinase. Bacteria can have dozens or even hundreds of these protein pairs relaying different signals.

About 10 years ago, Laub showed that the specificity between bacterial kinases and their substrates is determined by only five amino acids in each of the partner proteins. This raised the question of whether cells have already used up, or are coming close to using up, all of the possible unique combinations that won’t interfere with existing pathways.

Some previous studies from other labs had suggested that the possible number of interactions that would not interfere with each other might be running out, but the evidence was not definitive. The MIT researchers decided to take a systematic approach in which they began with one pair of existing E. coli signaling proteins, known as PhoQ and PhoP, and then introduced mutations in the regions that determine their specificity.

This yielded more than 10,000 pairs of proteins. The researchers tested each kinase to see if they would activate any of the substrates, and identified about 200 pairs that interact with each other but not the parent proteins, the other novel pairs, or any other type of kinase-substrate family found in E. coli.

“What we found is that it’s pretty easy to find combinations that will work, where two proteins interact to transduce a signal and they don’t talk to anything else inside the cell,” Laub says.

He now plans to try to reconstruct the evolutionary history that has led to certain protein pairs being used by cells while many other possible combinations have not naturally evolved.

Synthetic circuits

This study also offers a new strategy for creating new synthetic biology circuits based on protein pairs that don’t crosstalk with other cellular proteins, the researchers say. To demonstrate that possibility, they took one of their new protein pairs and modified the kinase so that it would be activated by a plant hormone called trans-zeatin, and engineered the substrate so that it would glow yellow when the kinase activated it.

“This shows that we can overcome one of the challenges of putting a synthetic circuit in a cell, which is that the cell is already filled with signaling proteins,” Voigt says. “When we try to move a sensor or circuit between species, one of the biggest problems is that it interferes with the pathways already there.”

One possible application for this new approach is designing circuits that detect the presence of other microbes. Such circuits could be useful for creating probiotic bacteria that could help diagnose infectious diseases.

“Bacteria can be engineered to sense and respond to their environment, with widespread applications such as ‘smart’ gut bacteria that could diagnose and treat inflammation, diabetes, or cancer, or soil microbes that maintain proper nitrogen levels and eliminate the need for fertilizer. To build such bacteria, synthetic biologists require genetically encoded ‘sensors,’” says Jeffrey Tabor, an associate professor of bioengineering and biosciences at Rice University.

“One of the major limitations of synthetic biology has been our genetic parts failing in new organisms for reasons that we don’t understand (like cross-talk). What this paper shows is that there is a lot of space available to re-engineer circuits so that this doesn’t happen,” says Tabor, who was not involved in the research.

If adapted for use in human cells, this approach could also help researchers design new ways to program human T cells to destroy cancer cells. This type of therapy, known as CAR-T cell therapy, has been approved to treat some blood cancers and is being developed for other cancers as well.

Although the signaling proteins involved would be different from those in this study, “the same principle applies in that the therapeutic relies on our ability to take sets of engineered proteins and put them into a novel genomic context, and hope that they don’t interfere with pathways already in the cells,” McClune says.

The research was funded by the Howard Hughes Medical Institute, the Office of Naval Research, and the National Institutes of Health Pre-Doctoral Training Grant.

Ankur Jain awarded Packard Foundation Fellowship

Whitehead Institute member and assistant professor of biology receives one of the most prestigious non-governmental awards for early-career scientists.

Merrill Meadow | Whitehead Institute
October 23, 2019

The David and Lucile Packard Foundation has announced that Ankur Jain, Whitehead Institute member and assistant professor of biology at MIT, has been named a Packard Fellow for Science and Engineering. The Packard Foundation Fellowships are one of the most prestigious and well-funded non-governmental awards for early-career scientists.

Each year, the foundation invites 50 university presidents to nominate two early-career professors each from their institutions; from those 100 nominees, an advisory panel of distinguished scientists and engineers select the fellows, who receive individual grants of $875,000 over five years. The 2019 class comprises 22 fellows.

“We are extraordinarily pleased that Ankur has received such clear and substantive affirmation of his pioneering research on the role that RNAs play in devastating neurological diseases,” says Whitehead Institute Director David C. Page. “This exciting work is at the forefront of soft-matter physics and cell biology, and could well open new chapters in RNA regulation specifically and in cell biology more broadly.”

“I am very grateful for the Packard Foundation’s support of our continued investigations of how RNA aggregation contributes to disease,” says Jain.

Jain has discovered that certain RNAs can form aggregates, clumping together into membrane-less gels. This process, known as phase separation, has been widely studied in proteins, but not in RNA. He has found that RNA gels occur in, and could contribute to, a set of neurological conditions such as amyotrophic lateral sclerosis and Huntington’s disease. These conditions, known as repeat expansion diseases, are marked by abnormal repetition of short sequences of nucleotides, the building blocks of DNA and RNA. The RNAs containing these sequences are more likely to clump together.

The fellowship will enable Jain to advance his research program around this phenomenon. “Although it is well-appreciated that RNA can form aggregates in test tubes, the biological implications of this process are not yet known,” he explains. “The award will allow us to examine how RNA aggregates affect cell function and ultimately contribute to neurological disease.”

Jain joined Whitehead Institute and MIT in 2018, after conducting postdoctoral research in the lab of Ronald Vale at the University of California at San Francisco. He earned a doctorate in biophysics and computational biology at University of Illinois at Urbana-Champaign in 2013, and received his bachelor’s degree (with honors) in biotechnology and biochemical engineering from Indian Institute of Technology Kharagpur in 2007.

Past Packard Fellows have gone on to receive a range of accolades, including the Nobel Prize in chemistry and physics, the Fields Medal, the Alan T. Waterman Award, MacArthur Fellowships, and elections to the National Academies. They include Frances Arnold, recipient of the 2018 Nobel Prize in Chemistry, who chairs the Packard Fellowships Advisory Panel, and Sangeeta Bhatia, the John and Dorthy Wilson Professor of Health Sciences and Technology at MIT, who is a member of all three National Academies (science, engineering, and medicine).

Two from MIT elected to the National Academy of Medicine for 2019

Sangeeta Bhatia and Richard Young recognized for their contributions to “advancement of the medical sciences, health care, and public health.”

Anne Trafton | MIT News Office
October 21, 2019

Sangeeta Bhatia, an MIT professor of electrical engineering and computer science and of health sciences and technology, and Richard Young, an MIT professor of biology, are among the 100 new members elected to the National Academy of Medicine today.

Bhatia is already a member of the National Academies of Science and of Engineering, making her just the 25th person to be elected to all three national academies. Earlier this year, Paula Hammond, head of MIT’s Department of Chemical Engineering, also joined netbet sports bettingthat exclusive group; MIT faculty members Emery Brown, Arup Chakraborty, James Collins, and Robert Langer have also achieved that distinction.

Bhatia, who is a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science, develops micro- and nanoscale technologies to improve human health. She has designed nanoparticles and other materials to diagnose and treat disease, including cancer, and she has also engineered human microlivers that can be used to model liver disease and test new drugs. She and her students have founded several biotechnology companies to further develop these technologies.

Young, who is a member of MIT’s Whitehead Institute for Biomedical Research, studies the regulatory circuitry that controls cell state and differentiation. His lab uses experimental and computational techniques to determine how signaling pathways, transcription factors, chromatin regulators, and small RNAs control gene expression. Since defects in gene expression can cause diabetes, cancer, hypertension, immune deficiencies, neurological disorders, and other health issues, improved understanding of this circuitry should lead to new insights into disease mechanisms and the development of new diagnostics and therapeutics.

“I am humbled to have been elected to the National Academy of Medicine,” Young says. “More than just a personal honor, it is an affirmation of the importance of basic biomedical research to understanding, preventing, and treating disease.”

Young was also elected to the National Academy of Science in 2012.

Bhatia and Hammond, both of whom have spent most of their careers at MIT, are now the only two women of color to belong to all three of the National Academies.

“I’m incredibly honored to be part of this group of thinkers and doers that I have long admired,” says Bhatia, the John and Dorothy Wilson Professor of Electrical Engineering and Computer Science. “I’m grateful to have been supported by MIT for decades and to have benefited from the gender equity movement that Nancy Hopkins and colleagues initiated in the 90s. My position, salary, promotion trajectory, space, leadership opportunities, and sense of community with amazing people like Paula are all the products of deliberate, hard work to overcome systemic unconscious bias. I hope we can serve as examples of what is possible for the next generation of researchers and the institutions that support them.”

“I am delighted to share this honor with my wonderful colleague, Sangeeta,” Hammond says. “We have truly benefited from the hard work of so many of our colleagues here at MIT who have stood up and voiced the importance of equity among scholars across race, culture, and gender. MIT has been an incredible place for me to further my career and to find outstanding male and female colleagues who continuously uplift and support each other. It is through the constant efforts we make together as a community to become a better place that we create opportunities for current and future scholars to shine.”

The National Academy of Medicine, established in 1970 as the Institute of Medicine, is an independent organization of eminent professionals from fields including health and medicine, as well as the natural, social, and behavioral sciences. Election to the National Academy of Medicine is considered one of the highest honors in the fields of health and medicine and recognizes individuals who have demonstrated outstanding professional achievement and commitment to service.